Subtyping Burkitt Lymphoma by <scp>DNA</scp> Methylation

Burkitt lymphoma (BL) is an aggressive germinal center B-cell-derived malignancy. Historically, sporadic, endemic, and immunodeficiency-associated variants were distinguished, which differ in the frequency of Epstein-Barr virus (EBV) positivity. Aiming to identify subgroups based on DNA methylation patterns, we here profiled 96 BL cases, 17 BL cell lines, and six EBV-transformed lymphoblastoid cell lines using Illumina BeadChip arrays. DNA methylation analyses clustered the cases into four subgroups: two containing mostly EBV-positive cases (BL-mC1, BL-mC2) and two containing mostly EBV-negative cases (BL-mC3, BL-mC4). The subgroups BL-mC1/2, enriched for EBV-positive cases, showed increased DNA methylation, epigenetic age, and, in part, proliferation history compared to BL-mC3/4. CpGs hypermethylated in EBV-positive BLs were enriched for polycomb repressive complex 2 marks, while the CpGs hypomethylated in EBV-negative BLs were linked to, for example, B-cell receptor signaling. EBV-associated hypermethylation affected regulatory regions of genes frequently mutated in BL (e.g., CCND3, TP53) and impacted superenhancers. This finding suggests that hypermethylation may compensate for the lower mutational burden of pathogenic drivers in EBV-positive BLs. Though minor, significant differences were also observed between EBV-positive endemic and sporadic cases (e.g., at the SOX11 and RUNX1 loci). Our findings suggest that EBV status, rather than epidemiological variants, drives the DNA methylation-based subgrouping of BL.

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Publication Details

Journal
Genes Chromosomes and Cancer
Published
2025-04-01
DOI
https://doi.org/10.1002/gcc.70042
Citations
6
Primary Topic
Viral-associated cancers and disorders
Type
article
Field-Weighted Citation Impact
6.27

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article

Subtyping Burkitt Lymphoma by DNA Methylation

Bernhard Radlwimmer, Daniel Hübschmann, Susanne Bens, Markus Kreuz et al.
6 citations
Genes Chromosomes and Cancer
Viral-associated cancers and disorders
6.27
article

Subtyping Burkitt Lymphoma by DNA Methylation

Bernhard Radlwimmer, Daniel Hübschmann, Susanne Bens, Markus Kreuz, Monika Szczepanowski, Michael Hummel, Shaymaa Elgaafary, Ole Ammerpohl, Maciej Rosołowski, Andreas Rosenwald, Reiner Siebert, Julia Kolarova, Arndt Borkhardt, Selina Glaser, Stephan Wolf, Coral del Val, Stefano Lazzi, Markus Löffler, Kishor G. Bhatia, Cristina López, Wilhelm Wößmann, Lorenzo Leoncini, Birgit Burkhardt, José‐Tomás Navarro, Janet Neequaye, Sam M. Mbulaiteye, Timothy Onyuma, Steve Hoffmann, Noel Onyango, Matthias Schlesner, Marius Rohde, Gustavo Tapia, Rabea Wagener, Helene Kretzmer, Ralf Küppers, Maria João Baptista, Wolfram Klapper, Peter Lichter, G. Ott, Lorenz Trümper
article en
6 citations

Abstract

Burkitt lymphoma (BL) is an aggressive germinal center B-cell-derived malignancy. Historically, sporadic, endemic, and immunodeficiency-associated variants were distinguished, which differ in the frequency of Epstein-Barr virus (EBV) positivity. Aiming to identify subgroups based on DNA methylation patterns, we here profiled 96 BL cases, 17 BL cell lines, and six EBV-transformed lymphoblastoid cell lines using Illumina BeadChip arrays. DNA methylation analyses clustered the cases into four subgroups: two containing mostly EBV-positive cases (BL-mC1, BL-mC2) and two containing mostly EBV-negative cases (BL-mC3, BL-mC4). The subgroups BL-mC1/2, enriched for EBV-positive cases, showed increased DNA methylation, epigenetic age, and, in part, proliferation history compared to BL-mC3/4. CpGs hypermethylated in EBV-positive BLs were enriched for polycomb repressive complex 2 marks, while the CpGs hypomethylated in EBV-negative BLs were linked to, for example, B-cell receptor signaling. EBV-associated hypermethylation affected regulatory regions of genes frequently mutated in BL (e.g., CCND3, TP53) and impacted superenhancers. This finding suggests that hypermethylation may compensate for the lower mutational burden of pathogenic drivers in EBV-positive BLs. Though minor, significant differences were also observed between EBV-positive endemic and sporadic cases (e.g., at the SOX11 and RUNX1 loci). Our findings suggest that EBV status, rather than epidemiological variants, drives the DNA methylation-based subgrouping of BL.

Genes Chromosomes and CancerVol. 64(4)
University of Siena (IT), Universitat Autònoma de Barcelona (ES), University of Nairobi (KE), National Institutes of Health (US), University of Ghana (GH), Hasso Plattner Institute (DE), Universität Hamburg (DE), Universidad de Granada (ES), University of Potsdam (DE), University of Augsburg (DE), German Cancer Research Center (DE), Universität Ulm (DE), Justus-Liebig-Universität Gießen (DE), Heidelberg University (DE), University of Würzburg (DE), Kenyatta National Hospital (KE), Robert Bosch Hospital (DE), Christian-Albrechts-Universität zu Kiel (DE), German Center for Pediatric and Adolescent Rheumatology (DE), Josep Carreras Leukaemia Research Institute (ES), Instituto Andaluz de Ciencias de la Tierra (ES), German Cancer Society (DE), University Hospital Münster (DE), Institut Català d'Oncologia (ES), University Medical Center Hamburg-Eppendorf (DE), University Hospital Schleswig-Holstein (DE), Instituto de Investigación Biosanitaria de Granada (ES), Hospital Clínic de Barcelona (ES), Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE), Complejo Hospitalario Universitario de Granada (ES), Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE), German Center for Lung Research (DE), National Cancer Institute (US), Max Planck Institute for Molecular Genetics (DE), Heidelberg Institute for Stem Cell Technology and Experimental Medicine (DE), Hospital Universitari Germans Trias i Pujol (ES), Deutsches Konsortium für Translationale Krebsforschung (DE), Heinrich Heine University Düsseldorf (DE), University of Duisburg-Essen (DE), University of Göttingen (DE), Friedrich Schiller University Jena (DE), Charité - Universitätsmedizin Berlin (DE), Leipzig University (DE), University of Lübeck (DE)
U.S. Department of Health and Human Services, Deutsches Krebsforschungszentrum, Friedrich-Schiller-Universität Jena, Università degli Studi di Siena, European Commission, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Christian-Albrechts-Universität zu Kiel, Georg-August-Universität Göttingen, Universität Potsdam, Ministerio de Ciencia e Innovación, University of Ghana, Universidad de Granada, Universität Duisburg-Essen, Julius-Maximilians-Universität Würzburg, Universität Ulm, Deutsches Zentrum für Lungenforschung, Universitat Autònoma de Barcelona, Deutschen Konsortium für Translationale Krebsforschung, National Institutes of Health, Leibniz-Gemeinschaft, Agencia Estatal de Investigación, Universitätsklinikum Hamburg-Eppendorf, Institut de Recerca contra la Leucèmia Josep Carreras, National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Cancer Institute
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Openalex Percentile: Top 3%
Viral-associated cancers and disorders
6.27
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